Development and validation of LC-MS/MS methods for the pharmacokinetic assessment of the PROTACs bavdeglutamide (ARV-110) and vepdegestrant (ARV-471).

Autor: Niessen J; Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala, Sweden., Nilsson JM; Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden., Peters K; Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala, Sweden., Indulkar A; AbbVie Research and Development, 1N Waukegan Road, North Chicago, IL, USA., Borchardt T; AbbVie Research and Development, 1N Waukegan Road, North Chicago, IL, USA., Koziolek M; Abbvie Deutschland GmbH & Co. KG, Small Molecule CMC Development, Knollstrasse, Ludwigshafen, Germany., Lennernäs H; Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala, Sweden., Dahlgren D; Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala, Sweden., Hedeland M; Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden. Electronic address: mikael.hedeland@ilk.uu.se.
Jazyk: angličtina
Zdroj: Journal of pharmaceutical and biomedical analysis [J Pharm Biomed Anal] 2024 Oct 15; Vol. 249, pp. 116348. Date of Electronic Publication: 2024 Jul 09.
DOI: 10.1016/j.jpba.2024.116348
Abstrakt: Chemically induced, targeted protein degradation with proteolysis targeting chimeras (PROTACs) has shown to be a promising pharmacological strategy to circumvent the poor "druggability" of intracellular targets. However, the favorable pharmacology comes with complex molecular properties limiting the oral bioavailability of these drugs. To foster the translation of PROTACs into the clinics it is of high importance to establish sensitive bioanalytical methods that enable the assessment of absorption, bioavailability, and disposition of PROTACs after oral dosing. In this study, two highly sensitive LC-MS/MS methods (LLOQ = 0.5 ng/mL) were developed and validated for the quantification of bavdeglutamide (ARV-110) and vepdegestrant (ARV-471) in rat plasma. Plasma samples were processed by protein precipitation and separated on a C18 column over a gradient of acetonitrile and water with 0.1 % formic acid. Selected reaction monitoring in positive ESI mode was applied to quantify ARV-110 and ARV-471. Both methods showed linearity, accuracy, and precision as well as matrix effects and carry-over within the predefined acceptance criteria. High stability of the compounds in plasma was demonstrated at long-term storage for seven weeks at -20 °C, three freeze-thaw cycles, up to 20 min at room temperature, and as extracts in the autosampler. The plasma concentration-time curves after intravenous and intraduodenal bolus single-dose administrations in rats could be successfully quantified at clinically relevant doses per body weight. The highly sensitive bioanalytical assays presented in this work enable the application of a broad spectrum of in vivo studies to elucidate the oral absorption, bioavailability, and disposition of PROTACs.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Dahlgren reports financial support was provided by AbbVie Inc. AI, TB and MK are employees of AbbVie and may own AbbVie stock. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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